This invention relates to a process for covalently coupling organic compounds, in particular to a process for covalently linking aromatic ring compounds via an organoboron intermediate to other organic compounds. The invention also relates to a process for the preparation of the organoboron intermediates.
Processes for forming covalent bonds between aromatic ring compounds and organic compounds, both inter- and intra-molecular, are of particular importance to the synthetic organic chemist. Many such reactions are known, each requiring its own special reaction conditions, solvents, catalysts, ring activating groups etc. Some known types of coupling reactions which can involve aromatic ring compounds include the Grignard reaction, Heck reactions and Suzuki reactions (N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483).
Catalysts of palladium, its complexes and its salts are well recognised for activation of Cxe2x80x94H bonds towards coupling reactions. In this regard the Heck reaction of an aryl halide with an aryl or vinyl halide in the presence of palladium derivatives has been the subject of intensive study. However commercial development of the Heck reaction has not progressed as rapidly as could have been expected. Other Group VIII metal catalysts, such as platinum, have also been used to activate such carbon bonds.
Substituted bi- and tri-aryl compounds are of great interest to the pharmaceutical and agrochemical industries. A great number of these compounds have been found to possess pharmaceutical activity, while others have been found to be useful herbicides. There is also interest from the polymer industry in polymers prepared by the linking together of aromatic ring compounds.
Conventional methods for covalently linking aromatic rings, such as by reaction of an appropriate Grignard reagent, involve harsh conditions and are not suitable for aromatic rings with active hydrogen containing substituents. Substituents with active hydrogen atoms also can become involved in unwanted side reactions leading to undesirable products. Such substituents need to be protected prior to reaction. Boronic acid derivatives required for the Suzuki reaction are traditionally synthesized through highly reactive organo metallic intermediates.
In view of the severity of the reaction conditions the range of substituents which could be present during the linking reaction was considerably limited, and the range of useful reaction media (solvents) was restricted to those which are generally expensive, difficult to remove and/or toxic.
Other difficulties associated with the known coupling reactions are the high temperatures required and the lack of control of the functionality of the products, leading to complex mixtures which can be difficult to separate.
It has now been found that coupling of aromatic ring compounds to other organic compounds can be achieved via an arylboron intermediate in the presence of a Group VIII metal catalyst and a suitable base.
Accordingly the invention provides a process for covalently coupling organic compounds which comprises reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base.
In one embodiment this process may be used to prepare a symmetrical product by reacting the diboron derivative with about two equivalents of aromatic ring compound. In this embodiment the coupling proceeds in two steps. In the first step the diboron derivative reacts with about one equivalent of aromatic ring compound in the presence of the Group VIII metal catalyst and suitable base to form an arylboron intermediate, which intermediate reacts in the presence of base with the remaining equivalent of aromatic ring compound. According to this embodiment the covalent coupling comprises a covalent bond between ring coupling positions of two molecules of aromatic ring compound.
Preferably the suitable base used to catalyse the reaction with the boron derivative is also able to catalyse the coupling of the arylboron intermediate to the remaining aromatic compound. However, if necessary, a stronger base can be added after the formation of the arylboron intermediate to catalyse the coupling reaction.
The process according to the invention also allows the preparation of unsymmetrical products. Accordingly in another embodiment of the invention there is provided a process for covalently coupling organic compounds which comprises:
reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII catalyst and a suitable base to form an arylboron intermediate, and
reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the aromatic ring compound is coupled to the organic compound via a direct bond between the respective coupling positions.
The process according to this embodiment allows the preparation of unsymmetrical compounds when the organic compound is different from the aromatic ring compound, although symmetrical products will be obtained if the organic compound is the same as the aromatic ring compound.
It is especially convenient to conduct the process in a single pot without isolation of the arylboron intermediate, however it has been found that the presence of unreacted diboron derivative can interfere with the coupling step, resulting in the formation of unwanted by-products.
Accordingly in another embodiment of the present invention there is provided a process for covalently coupling organic compounds which comprises:
reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate,
adding water and a suitable base to decompose excess diboron derivative,
reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the aromatic ring compound is coupled to the organic compound via a direct bond between respective coupling positions.
Preferably the reaction is conducted in a single pot, although it is possible to isolate the arylboron intermediate prior to the final coupling step. If the reaction is conducted in a single pot it is preferred that the base added to decompose the diboron derivative is suitable for catalysing the coupling reaction. In this case there is no need to add further base with the organic compound in the coupling reaction.
In cases where there is a need to remove excess diboron derivative but the use of water and/or base is deleterious because of the sensitivity of substituents, etc, or other factors the excess diboron derivative may be decomposed by addition of mild oxidising agents following the formation of the arylboron intermediate.
Accordingly in a further embodiment there is provided a process for covalently coupling organic compounds which comprises:
reacting an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position with a diboron derivative in the presence of a Group VIII
metal catalyst and a suitable base to form an arylboron intermediate;
adding a mild oxidising agent to decompose excess diboron derivative;
reacting the arylboron intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base whereby the aromatic ring compound is coupled to the organic compound via a direct bond between respective coupling positions.
The mild oxidising agent may be any compound which will break the Bxe2x80x94B bond of the diboron derivative but which is not strong enough to break boron-carbon bonds of the arylboron intermediate. Suitable mild oxidising agents are N-chlorosuccinimide, dimethyl dioxirane, dioxygen gas, chloramine-T, chloramine-B, 1-chlorotriazole, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid and dichloroisocyanuric acid potassium salt.
Oxidants such as hydrogen peroxide, ozone, bromine, t-butyl hydroperoxide, potassium persulphate, sodium hypochlorite and peracids, are too strong for use in this process; use of strong oxidants does not form part of this invention.
The term xe2x80x9caromatic ring compound(s)xe2x80x9d as used herein refers to any compound which includes or consists of one or more aromatic or pseudoaromatic rings. The rings may be carbocyclic or heterocyclic, and may be mono or polycyclic ring systems. Examples of suitable rings include but are not limited to benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetrahydronaphthalene, 1-benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthracene, perylene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, thianthrene, furan, pyrene, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, indole, indolizine, isoindole, purine, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, isothiazole, isooxazole, phenoxazine and the like, each of which may be optionally substituted. The term xe2x80x9caromatic ring compound(s)xe2x80x9d includes molecules, and macromolecules, such as polymers, copolymers and dendrimers which include or consist of one or more aromatic or pseudoaromatic rings. The term xe2x80x9cpseudoaromaticxe2x80x9d refers to a ring system which is not strictly aromatic, but which is stablized by means of delocalization of xcfx80 electrons and behaves in a similar manner to aromatic rings. Examples of pseudoaromatic rings include but are not limited to furan, thiophene, pyrrole and the like.
As used herein the term xe2x80x9corganic compound having a halogen or halogen-like substituent at a coupling positionxe2x80x9d refers to any organic compound having a carbon to halogen or carbon to halogen-like substituent bond at a position where coupling to the aromatic ring compound is desired. The organic compound may be aliphatic, olefinic, aromatic, polymeric or dendritic. The compound may be an aromatic ring compound as defined above or part of such an aromatic ring compound. The organic compound may have one or more, preferably between 1 and 6, halogen or halogen-like substituents at coupling positions.
The terms xe2x80x9colefinicxe2x80x9d and xe2x80x9colefinic compoundxe2x80x9d as used herein refer to any organic compound having at least one carbon to carbon double bond which is not part of an aromatic or pseudo aromatic system. The olefinic compounds may be selected from optionally substituted straight chain, branched or cyclic alkenes; and molecules, monomers and macromolecules such as polymers and dendrimers, which include at least one carbon to carbon double bond. Examples of suitable olefinic compounds include but are not limited to ethylene, propylene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, cyclopentene, 1-methylpent-2-ene, hex-1-ene, hex-2-ene, hex-3-ene, cyclohexene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, cyclooctene, non-1-ene, non-4-ene, dec-1-ene, dec-3-ene, buta-1,3-diene, penta-1,4-diene, cyclopenta-1,4-diene, hex-1,diene, cyclohexa-1,3-diene, cyclohexa-1,4-diene, cyclohepta-1,3,5-triene and cycloocta-1,3,5,7-tetraene, each of which may be optionally substituted. Preferably the straight chain branched or cyclic alkene contains between 2 and 20 carbon atoms.
In one embodiment the organic compound is an olefinic compound of formula I 
where R, R2 and R3 are each independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, arylalkyl and heteroaryalkyl, each of which may be optionally substituted: and cyano, isocyano, formyl, carboxyl, nitro, halo, alkoxy, alkenoxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitroalkyl, nitroalkenyl, nitroalkynyl, arylamino, diarylamino, dibenzylamino, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocycloxy, arylsulphenyl, carboalkoxy, carboaryloxy, alkylthio, benzylthio, acylthio, sulphonamide, sulfanyl, sulfo, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sulfamyl, phosphorous containing groups (including phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphone (including phosphonato) and hydrohydroxyphosphoryl), guanidinyl, duanidino, ureido and ureylene, and X is a halogen or halogen-like substituent.
The term xe2x80x9ccoupling positionxe2x80x9d as used herein refers to a position on an aromatic ring compound at which coupling to an organic compound is desired. A coupling position on a ring of an aromatic ring compound is also referred to as a xe2x80x9cring coupling positionxe2x80x9d. The term xe2x80x9ccoupling positionxe2x80x9d also refers to a position on an organic compound at which coupling to an aromatic ring compound is desired. Each aromatic ring compound or organic compound may have one or more, preferably between 1 and 6, coupling positions.
In this specification xe2x80x9coptionally substitutedxe2x80x9d means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, isocyano, cyano, formyl, carboxyl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, imino, alkylimine, alkenylimine, alkynylimino, arylimino, benzylimino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alkylthio, benzylthio, acylthio, sulphonamido, sulfanyl, sulfo and phosphorus-containing groups, alkoxysilyl, silyl, alkylsilyl, alkylalkoxysilyl, phenoxysilyl, alkylphenoxysilyl, alkoxyphenoxy silyl and arylphenoxy silyl.
The aromatic ring compound must include at least one halogen or halogen-like substituent at a ring coupling position to enable reaction with the diboron derivative. Similarly the organic compound must have at least one halogen or halogen-like substituent at a coupling position to enable reaction with the arylboron intermediate. Preferred halogen substituents include I and Br. Cl may also be used although Cl is generally less reactive to substitution by the boron derivative or aryl boron intermediate. The reactivity of chloro substituted aromatic ring compounds can be increased by selection of appropriate ligands on the Group VIII metal catalyst. The terms xe2x80x9chalogen-like substituentxe2x80x9d and xe2x80x9cpseudo-halidexe2x80x9d refer to any substituent which, if present on an aromatic ring, may undergo substitution with a diboron derivative in the presence of a Group VIII metal catalyst and base to give an arylboron intermediate, or if present on an organic compound may undergo substitution with an arylboron intermediate to give a coupled product. Examples of halogen-like substituents include triflates and mesylates, diazonium salts, phosphates and those described in Palladium Reagents and Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley and Sons, 1995, ISBN 0-471-95483-7).
The process according to the invention is especially suitable for coupling aromatic ring compounds which have active hydrogen containing substituents on the aromatic ring(s) to be coupled. The term xe2x80x9cactive hydrogen containing substituentxe2x80x9d as used herein refers to a substituent which contains a reactive hydrogen atom. Examples of such substituents include but are not limited to hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene. Of these substituents it is particularly surprising that the reaction can be conducted with hydroxy and amino substituents in view of their high reactivity. Carboxyl, sulfo and the like (i.e. acidic) substituents may require additional base.
In the above definitions, the term xe2x80x9calkylxe2x80x9d, used either alone or in compound words such as xe2x80x9calkenyloxyalkylxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d and xe2x80x9cdialkylaminoxe2x80x9d denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3,-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-,2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propylocytl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term xe2x80x9calkoxyxe2x80x9d denotes straight chain or branched alkoxy, preferably C1-20 alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy isomers.
The term xe2x80x9calkenylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C2-20 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1-4, pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.
The term xe2x80x9calkynylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkyne including alkyl and cycloalkyl groups as previously defined which contain a triple bond, preferably C2-20 alkynyl. Examples of alkynyl include ethynyl, 2,3-propynyl and 2,3- or 3,4-butynyl.
The term xe2x80x9cacylxe2x80x9d either alone or in compound words such as xe2x80x9cacyloxyxe2x80x9d, xe2x80x9cacylthioxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d or xe2x80x9cdiacylaminoxe2x80x9d denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl, preferably C1-20 acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylearbonyl and cyclohexylcarbonyt; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethaeryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and napthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienylglyoxyloyl.
The terms xe2x80x9cheterocycic, heterocyclylxe2x80x9d and xe2x80x9cheterocyclxe2x80x9d as used herein on their own or as part of a group such as xe2x80x9cheterocyclicalkenoylxe2x80x9d, heterocycloxyxe2x80x9d or xe2x80x9chaloheterocyclylxe2x80x9d refer to aromatic, pseudo-aromatic and non-aromatic rings or ring systems which contain one or more heteroatoms selected from N, S, O and P and which may be optionally substituted. Preferably the rings or ring systems have 3 to 20 carbon atoms. The rings or ring systems may be selected from those described above in relation to the definition of xe2x80x9caromatic ring compound(s)xe2x80x9d.
The term xe2x80x9carylxe2x80x9d as used herein on its own or as part of a group such as xe2x80x9chaloarylxe2x80x9d and xe2x80x9caryloxycarbonylxe2x80x9d refers to aromatic and pseudo-aromatic rings or ring systems composed of carbon atoms, optionally together with one or more heteroatoms. Preferably the rings or ring systems have between 3 and 20 carbon atoms. The rings or ring systems may be optionally substituted and may be selected from those described above in relation to the definition of xe2x80x9caromatic ring compound(s)xe2x80x9d.
The diboron derivative may be an ester or other stable derivative of diboronic acid. Examples of suitable esters include those of the formula (RO)2Bxe2x80x94B(RO)2 where R is optionally substituted alkyl or optionally substituted aryl or xe2x80x94B(OR)2 represents a cyclic group of formula 
where Rxe2x80x2 is optionally substituted alkylene, arylene or other divalent group comprising linked aliphatic or aromatic moieties. Preferred diboron derivatives include the pinacol ester of diboronic acid, bis(ethanediolato)diboron, bis(n-propanediolato)diboron and bis(neopentanediolato)diboron. Some of the diboron derivatives will be more readily amenable to subsequent hydrolysis than others and may allow for the use of milder reaction conditions. Furthermore, judicious choice of the diboron derivative used may facilitate control over the reaction products formed. The diboron ester derivatives may be made following the method of Brotherton et al. [R. J. Brotherton, A. L. McCloskey, L. L. Peterson and H. Steinberg, J. Amer. Chem. Soc. 82, 6242 (196); R. J. Brotherton, A. L. McCloskey, J. L. Boone and H. M. Manasevit, J. Amer. Chem. Soc. 82, 6245 (1960)]. In this process B(NMe2)3, obtained by reaction of BCl3 with NHMe2, is converted to BrB(NMe2)2 by reaction with a stoichiometric amount of BBr3. Reduction in refluxing toluene with sodium metal gives the diboron compound [B(NMe2)2]2 which, after purification by distillation, can be reacted with the alcohol (for example, pinacol) in the presence of a stoichiometric amount of HCl to give the desired ester product. Bis(neopentanediolato)diboron is described by Nguyen et al [Nguyen, P., Lesley, G., Taylor, N. J., Marder, T. B., Pickett, N/L/, Clegg, W., Elsegood, M. R. J., and Norman, N. C., Inorganic Chem. 1994, 33, 4623-24]. Other methods for the preparation of the diboron derivatives would be known to those in the art. The diboron derivatives in Examples 1, 2 and 3 are known, but their use in the formation of aryl boron intermediates has not been disclosed.
The term xe2x80x9cGroup VIII metal catalystxe2x80x9d as used herein refers to a catalyst comprising a metal of Group VIII of the periodic table described in Chemical and Engineering News, 63(5), 27, 1985. Examples of such metals include Ni, Pt and Pd. Preferably the catalyst is a palladium catalyst as described below, although analogous catalysts of other Group VIII metals may also be used. Examples of suitable Ni catalysts include nickel black, Raney nickel, nickel on carbon and nickel clusters.
The palladium catalyst may be a palladium complex. Examples of suitable palladium catalysts include but are not limited to PdCl2, Pd(OAc)2, PdCl2(dppf)CH2Cl2, Pd(PPh3)4, Pd(Ph2P(CH2)nPPh2) where n is 2 to 4 and related catalysts which are complexes phosphine ligands, (such as P(o-tolyl)3, P(i-Pr)3, P(cyclohexyl)3, P(o-MeOPh)3, P(p-MeOPh)3, dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP and related water soluble phosphines), related ligands (such as triarylarsine, triarylantimony, triarylbismuth), phosphite ligands (such as P(OEt)3, P(O-p-tolyl)3, P(O-o-tolyl)3 and P(O-iPr)3) and other suitable ligands including those containing P and/or N atoms for coordinating to the palladium atoms, (such as for example pyridine, alkyl and aryl substituted pyridines, 2,2xe2x80x2-bipyridyl, alkyl substituted 2,2xe2x80x2-bipyridyl and bulky secondary or tertiary amines), and other simple palladium salts either in the presence or absence of ligands. The palladium catalysts include palladium and palladium complexes supported or tethered on solid supports, such as palladium on carbon, as well as palladium black, palladium clusters, palladium clusters containing other metals, and palladium in porous glass described in J. Li, A. W-H. Mau and C. R. Strauss, Chemical Communications, 1997, p1275. The same or different palladium catalysts may be used to catalyse different steps in the process. In certain reactions there are advantages in using ligands with altered basicity and/or steric bulk.
The process may be performed in any suitable solvent or solvent mixture. Examples of such solvents include amides of the lower aliphatic carboxylic acids and lower aliphatic secondary amines, DMSO, aromatic hydrocarbons, nitromethane, acetonitrile, benzonitrile, ethers, polyethers, cyclic ethers, lower aromatic ethers, lower alcohols, and their esters with the lower aliphatic carboxylic acids, pyridine, alkylpyridines, cyclic and the lower secondary and tertiary amines, and mixtures thereof, including mixtures with other solvents.
In a preferred embodiment of the invention the process is performed in a protic solvent. Examples of suitable protic solvents include water and lower alcohols. Most preferably the solvent is water, ethanol, methanol, isopropanol or mixtures thereof with other solvents. Particularly preferred solvents are ethanol and methanol. Strict exclusion of water from the solvents is generally not essential. The addition of further diboron derivative has been found useful when the solvents are not anhydrous.
The temperature at which each step of the process according to the invention is conducted will depend on a number of factors including the desired rate of reaction, solubility and reactivity of the reactants in the selected solvent, boiling point of the solvent, etc. The temperature of the reaction will generally be in the range of xe2x88x92100 to 250xc2x0 C. In a preferred embodiment the process is performed at a temperature between 0 and 120xc2x0 C., more preferably between 0 and 80xc2x0 C., and most preferably between 15 and 40xc2x0 C.
The term xe2x80x9csuitable basexe2x80x9d as used herein refers to a basic compound which, when present in the reaction mixture, is capable of catalysing, promoting or assisting reaction-between reactants. The base may be suitable for catalysing a single step, or more than one step, depending on the desired outcome of the reaction. For example a base may be chosen which catalyses reaction between the aromatic ring compound and the diboron derivative, but which is not strong enough to catalyse further reaction of aryl boron intermediate with additional aromatic ring compound or other organic compound. In this case a stronger base (and water) may be added to decompose excess diboron derivative, and which may also catalyse reaction of the arylboron intermediate with the organic compound. It is also preferable that a base is chosen which is soluble in the solvent to which it is added. Examples of bases which are suitable for catalysing the reaction of the aromatic ring compound with the diboron derivative include, aryl and alkyl carboxylates (for example potassium acetate), fluorides, hydroxides and carbonates of Li, Na, K, Rb, Cs, ammonium, alkylammonium, Mg, Ca, and Ba; phosphates and arylphosphates of Li, Na, K, Rb and Cs; phosphate esters (eg. C6H5OP(O)(ONa)2) of Li, Na, K, Rb and Cs; phenoxides of Li, Na, K, Rb and Cs; alkoxides of Li, Na, K, Rb and Cs; and thallium hydroxide. Some of these bases may be used in conjunction with a phase transfer reagent, such as for example tetraalkylammonium salts or the crown ethers.
Examples of bases suitable for catalysing reaction of the aromatic ring compounds with the diboron derivative, without generally catalysing the further reaction of the arylboron intermediate, include aryl and alkyl carboxylates and phosphates of Li, Na, K, Rb, Cs, ammonium and alkylammonium.
Examples of bases suitable for decomposing excess diboron derivative and/or catalysing reaction of the arylboron intermediate include the stronger bases listed above, including caesium carbonate, potassium carbonate and alkali metal hydroxides.
The literature (cf. Miyaura et al., J. Org. Chem., 1995) describes the synthesis of arylboronic acid esters of pinacol using weak bases (viz. potassium acetate) at 80xc2x0 C. With strong bases, (e.g. potassium carbonate) dimer formation occurred, the Suzuki reaction competing strongly with arylboronic acid ester formation.
It has now surprisingly been found that strong bases can be used to synthesise organoboron intermediates, such as arylboronic acid esters near or below ambient temperatures in good yields with good selectivity compared to biaryl formation. The temperature of the reaction using the strong base can be selected such that further reaction of the intermediates with unreacted aromatic ring compound having halogen or halogen-like substituents is substantially prevented. This has the advantage that it enables the preparation of the arylboronic acid ester at low temperatures, important when the substituent(s) on the aryl ring can react (be reduced, rearranged, etc). A further advantage of these reactions employing stronger base to form the arylboronic acid ester is that the arylboronic acid ester may be coupled with aryl halides to give symmetric or asymmetric biaryls or with alkenyl halides to give styrryl type species without the requirement of adding a second (strong) base. The promotion of these Suzuki coupling reactions is therefore controlled primarily by reaction temperature, the temperature required depending upon the reactivity towards coupling of the added halide species and the sensitivity/stability of substituents on the reactants. For example, after formation of the arylboron intermediate, the temperature of the reaction medium can be raised to promote the coupling reaction. The temperature of the reaction with the diboron derivative is preferably conducted at a temperature below 40xc2x0 C., more preferably at or below ambient temperature.
As used herein the term xe2x80x9carylboron intermediatexe2x80x9d refers to the product of the Group VIII metal base catalysed reaction between an aromatic ring compound having a halogen or halogen-like substituent at a ring coupling position and a diboron derivative, the product including a carbon- to -boron bond at the ring coupling position. Examples of such intermediates include arylboronic acid esters.
In another aspect of the invention there is provided a process for preparing an arylboron intermediate comprising reacting a diboron derivative with an aromatic ring compound having a halogen or halogen-like substituent and an active hydrogen containing substituent in the presence of a Group VIII metal catalyst and a suitable base.
In a further aspect of the invention there is provided a process for preparing an arylboron intermediate, comprising reacting a diboron derivative with an aromatic ring compound having a halogen or halogen-like substituent in a protic solvent in the presence of a Group VIII metal catalyst and a suitable base.
A first step in the purification of the arylboron intermediate so formed may be the decomposition of any excess diboron derivative by the use of water, water and base, or by the use of a mild oxidising agent.
In a further aspect of the invention there is provided a process for the preparation of an aryl boronic acid including hydrogenolysing or hydrolysing the arylboron intermediate as hereinbefore described using established procedures. The ease of hydrolysis/hydrogenolysis is a function of the diboronic ester used. Some aryl boron intermediates are more amenable to hydrolysis/hydrogenolysis than those derived from the pinacol ester of diboronic acid. This method only relates to arylboron intermediates which are boronic esters.
Some of the arylboron intermediates and aryl boronic acids are novel and represent a further aspect of the present invention. Examples of such novel aryl boron intermediates which may be prepared according to the present invention are listed in Table 2, while some known arylboron intermediates prepared in accordance with the present invention are listed in Table 1.
The term xe2x80x9clinking groupxe2x80x9d as used herein refers to any chain of atoms linking one aryl group to another. Examples of linking groups include polymer chains, optionally substituted alkylene group and any other suitable divalent group.
The process according to the present invention is applicable to chemistry on solid polymer support or resin bead in the same manner as conventional chemistry is used in combinatorial chemistry and in the preparation of chemical libraries. Thus a suitable organic compound having a halogen or halogen-like substituent at a coupling position which is chemically linked to a polymer surface may be reacted with an arylboron intermediate in the presence of a Group VIII metal catalyst and a suitable base to form a coupled product linked to the surface of the polymer. Excess reagents and by-products may then be washed away from the surface leaving only the reaction product on the surface. The coupled product may then be isolated by appropriate cleavage of the chemical link from the polymer surface. The process is also possible using the alternative strategy of reacting an aromatic ring or an aromatic ring compound having a halogen or halogen-like substituent linked to a polymer surface with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate chemically linked to the polymer surface. This intermediate may then be reacted with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base to prepare the coupled product chemically linked to the polymer. Excess reactants and by-products may be removed by suitable washing and the coupled product may be isolated by chemically cleaving the link to the polymer.
In accordance with the present invention it is also possible to directly functionalise the surface of a polymer, e.g. polystyrene, with a halogen or halogen-like substituent and then convert this functionalised surface to an arylboron surface by reaction of the functionalised polymer with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base. The arylboron surface may then be reacted with any suitable organic compound having a halogen or halogen-like substituent. If the aromatic ring compound contains other functional groups, for example carboxylic ester, they may be used as linker groups to further extend the chemical reactions applied to the polymer surface.
It is also possible to prepare polyaryl compounds or other polymers by reaction of aromatic ring compounds having more than one halogen or halogen-like substituent. Such aromatic ring compounds may be reacted with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an arylboron intermediate having more than one boron functionality. These intermediates may be reacted with aromatic ring compounds or organic compounds having more than one halogen or halogen-like substituent to form a polymer. If the aromatic ring compound has three or more halogen or halogen-like substituents which react with the diboron derivative then it is possible to prepare dendritic molecules in accordance with the process of the present invention.
The aromatic ring compound and the organic compound may be separate molecules or may be linked together such that the arylboron intermediate formed after reaction with the diboron derivative is able to react at a coupling position located elsewhere in the molecule so as to provide for an intramolecular reaction, such as a ring closure reaction. Similarly the process according to the invention allows intramolecular linking to occur between different aromatic rings bearing halogen or halogen-like substituents located at different parts of the molecule. Reaction of one halide substituent with a diboron ester to form an arylboron intermediate allows reaction of that intermediate with the halide substituent on the other ring to thereby link the aromatic rings.
The process according to the invention is also useful for the preparation of reactive intermediates which are capable of taking part in further reactions or rearrangements. These reactive intermediates may be the aryl boron intermediates or the coupled products. The aryl boron intermediates may take part in one or more of the palladium catalysed reactions of aryl boron compounds described by Miyaura and Suzuki in Chem. Rev. 1995, 95 2457-2483.
The process according to the present invention allows the linking of aromatic rings and aromatic ring compounds to organic compounds in mild conditions and avoids the use of expensive, difficult to remove and/or toxic reagents and solvents. In this regard boron and boron compounds are generally non-toxic. The reactions may also be performed in relatively cheap solvents such as methanol and ethanol and, in view of the improved control over the reaction steps, it is envisaged that it would be possible to perform the reactions on an industrial scale. The process also allows the linking of aromatic rings which contain active hydrogen substituents without the need to protect those substituents during the reaction.